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Adrenocortical Steroid Metabolism and Adrenal Cortical Function in Liver Disease

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ADRENOCORTICAL STEROID METABOLISM AND ADRENAL CORTICAL FUNCTION IN LIVER DISEASE Ralph E. Peterson J Clin Invest. 1960;39(2):320-331. https://doi.org/10.1172/JCI104043. Research Article Find the latest version: https://jci.me/104043/pdf ADRENOCORTICAL STEROID METABOLISM AND ADRENAL CORTICAL FUNCTION IN LIVER DISEASE BY RALPH E. PETERSON * (From The National Institute of Arthritis and MVetabolic Diseases, Bethesda, Md.) (Submitted for publication July 27, 1959; accepted October 1, 1959) Zondek (1) as early as 1934 demonstrated that to man disappear rapidly from the blood (15, 16). enzymes of the liver destroyed the biological ac- Only minimal quantities are lost via the expired tivity of the estrogens. Since then both in tivo CO2 (17) or the biliary or gastrointestinal tract and in vitro studies have provided much evidence (15, 16). Also, practically all of the administered to show that the liver is the organ primarily re- steroid is metabolized prior to its excretion in the sponsible for the catabolism of the steroid hor- urine (15, 16), and thus it is apparent that urinary mones: estrogens, androgens, progesterone, and excretion plays a relatively minor part in elimi- the corticosteroids (2). However, not until the nating the biologically active steroid. Thus, meta- development of improved methods for measure- bolic transformation by the liver must play the pre- ment of certain of the adrenocortical steroids and dominant role in terminating the action of the their metabolites, and the availability of labeled steroids. radioactive cortisol, corticosterone, and aldosterone Because of the major role of the liver in the has it been possible accurately to evaluate the in- catabolism of the corticosteroids, it might be ex- fluence of liver disease on the rate of degradation pected that this organ could indirectly influence and synthesis of the steroids in man. The studies the synthesis of corticosteroids by the adrenals. here reported are based on the use of certain of Many investigators have attempted to determine these newer techniques. whether alterations in the functional capacity of the On incubation with rat liver tissue, cortisol and liver result in changes in adrenal cortical function. cortisone are rapidly metabolized, but only very Until recently studies of adrenal cortical function slowly with other tissues (3-5). Perfusion stud- in both acute and chronic liver disease were based ies have demonstrated a very rapid metabolism of on measurements of urinary steroids. There has the steroids by the liver but not by other organs been general agreement that the urinary 17-ke- (6-8). Hechter, Frank, Caspi and Frank (9) tosteroids are low in various forms of liver disease found that the major portion of the cortisone and -acute viral hepatitis (18-21), toxic hepatitis cortisol administered into the portal vein in dogs (20), portal cirrhosis (18-22), biliary cirrhosis was not recovered as unaltered steroid from the (23, 24), and also in obstructive jaundice (18-21, hepatic venous blood. Bradlow, Dobriner and 25). Urinary androgen excretion, as measured by Gallagher (10) found that 70 per cent of a dose of bioassay, has also been found to be low in cirrhosis tritium-labeled cortisone administered to mice of the liver (26, 27). However, since only a small was found in the liver within five minutes after fraction (5 to 10 per cent) of the cortisol is me- intravenous administration. Administered cortisol tabolized to 17-ketosteroids (28), the urinary also disappears rapidly from the circulation in rats level of this material does not represent an ade- (11), and this rapid metabolism can be prevented quate index of the functional capacity of the by hepatectomy but not by nephrectomy (12). adrenal cortex to secrete corticosteroids such as The liver in man has a high capacity for metabo- cortisol. Furthermore, the rate of adrenal cortical lizing the circulating blood cortisol, as demon- secretion of 17-ketosteroids may not always paral- strated by the fact that the level of 17-hydroxy- lel the rate of secretion of adrenal corticosteroids. corticosteroids in the hepatic vein blood is lower Although urine levels of "corticoids" have been than the level in the arterial blood (13, 14). reported to be normal or elevated in acute hepatitis Adrenocortical steroids administered intravenously (21) and cirrhosis (21, 23, 25, 29-31), the data are difficult to interpret because * Now at Cornell University Medical College, New in these studies York, N. Y. of the nonspecific methods of assay used. Brown, 320 ADRENAL FUNCTION IN LIVER DISEASE 321 Willardson, Samuels and Tyler (32), using a more specificity of this assay method for each steroid was eval- these ster- reliable assay method, found the urinary corticoids uated by isotope dilution (37).2 For each of oids, the isotope dilution assay indicated that at least 80 to be low in cirrhosis. Plasma 17-hydroxycorti- per cent of the steroid as measured by the phenylhydra- costeroid levels have been reported to be normal zine assay represented the administered steroid. in cirrhosis of the liver (33, 34). In other stud- The rate of disappearance of cortisol4-C'4 from the ies of cortisol metabolism in liver disease, infused plasma and its rate of appearance in the ascitic fluid cortisol was reported to disappear from the plasma was determined by the double labeling technique using cortisol-H' (42). The rate of disappearance of aldoster- at a decreased rate in patients with hepatitis or one from the plasma after infusion of aldosterone-H' was cirrhosis of the liver (15, 32, 33). determined by the double labeling technique using al- Studies of the adrenals in patients with cirrhosis dosterone and acetic-i-C14 anhydride (42). of the liver coming to autopsy have demonstrated Cortisone and corticosterone were determined by the a decrease in lipoid material (35) and narrow and isotope dilution method, since the phenylhydrazine assay for cortisone (43) and, to a lesser extent, the fluoro- frequently nodular adrenal cortices (36). metric assay for corticosterone (40) were not found to be specific for the determination of these steroids in MATERIALS AND METHODS plasma following their intravenous injection. Fourteen patients with moderately severe cirrhosis of Urine cortisol concentration following the infusion of the liver, as judged by clinical signs and symptoms and cortisol was determined by isotope dilution. Following liver function tests, and 3 patients with acute viral hepa- the injection of cortisol4-C'4, the total radioactivity in titis, served as the subjects of this study. Those with the urine was determined by counting a small aliquot of cirrhosis of the liver had the classical symptoms, signs, the urine (0.1 to 0.5 ml) in an alcohol-toluene, DPO and laboratory findings, viz. prolonged sulfobromoph- (diphenyloxyzol) and POPOP [1,4-bis-2- (5-phenyloxa- thalein retention, reversed albumin/globulin ratio with zolyl)-benzene] phosphor in the liquid scintillation spec- low serum albumin, elevated serum bilirubin, and ab- trometer. The fractions of radioactive metabolites ap- normal thymol turbidity or cephalin flocculation tests. pearing as free and glucuronide conjugates were de- On clinical grounds, most of these patients were presumed termined by previously described methods (15). The to have alcoholic cirrhosis, and in the majority of the urine concentrations of tetrahydrocortisol following in- subjects the diagnosis of cirrhosis was confirmed by nene-3, 20-dione). Aldosterone (11j, 21-dihydroxy4- liver biopsy. One of the 3 patients with acute hepatitis pregnene-3, 20-dione-18, al). Dihydrocortisone (17a, 21- had homologous serum (post-transfusion) hepatitis. dihydroxy-pregnane-3, 11, 20-trione). Dihydrocortisol Plasma cortisol and urinary corticosteroids were de- (ll,B, 17a, 21-trihydroxy-pregnane-3, 20-dione). Tetra- termined by the modified (37) procedure of Silber and hydrocortisone (3a, 17a, 21-trihydroxy-pregnane-11, 20- Porter (38) using phenylhydrazine and sulfuric acid. dione). Tetrahydrocortisol (3a, llfi, 17a, 21-tetrahy- Urinary 17-ketosteroids were determined by the Zimmer- droxy-pregnane-20-one). Tetrahydrocorticosterone (3a, mann procedure, modified from the Holtorff and Koch 11,, 21-trihydroxy-pregnane-20-one). 9a-Fluorocortisol method (39). Plasma corticosterone was determined by (9a-fluoro-ll,8,-7a, 21-trihydroxy4-pregnene-3, 20-di- an isotope dilution method (40). Aldosterone excretion one). A' 9a-Fluorocortisol (9a-fluoro-iip, 17a, 21-tri- in the urine was determined by the double isotope deriva- hydroxy-1,4-pregnene-3, 20-dione). tive method (41, 42). 2 mc for intravenous adminis- Cortisone-4-C'4 (0.49 per mmole), cortisol-4-C' The steroids (100 to 200 mg) (1.47 mc per mmole), corticosterone4-C'4 (1.47 mc per tration were dissolved in ethanol and diluted to 300 ml mmole), tetrahydrocortisone-4-C'4 monoacetate (0.4 mc per dextrose in water to a final alcohol con- with 5 cent per mmole), and dihydrocortisone-4-C' acetate (0.4 mc centration of approximately 5 per cent. Following of the steroids between per mmole) were obtained from the Endocrine Study rapid (10 to 15 minutes) infusion Section of the National Institutes of Health. The acetates 8 and 9 a.m., plasma samples were collected serially at 20 were converted to the free steroids by hydrolysis with for 2 to 3 hours and assayed. to 30 minute intervals acetyl cholinesterase as described previously (43). C'4- Plasma steroid concentration was plotted semilogarithmi- of the labeled tetrahydrocortisol and dihydrocortisol were pre-
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